Advancing Parkinson’s disease treatment: cell replacement therapy with neurons derived from pluripotent stem cells

Stem Cells, Год журнала: 2024, Номер 42(9), С. 781 - 790

Опубликована: Июнь 21, 2024

Abstract The motor symptoms of Parkinson’s disease (PD) are caused by the progressive loss dopamine neurons from substantia nigra. There currently no treatments that can slow or reverse neurodegeneration. To restore lost neurons, international groups have initiated clinical trials using human embryonic induced pluripotent stem cells (PSCs) to derive neuron precursors used as transplants replace neurons. Proof-of-principle experiments in 1980s and 1990s showed grafts fetal ventral mesencephalon, which contains substantial nigra, could, under rare circumstances, disease. Improvements PSC technology genomics inspired researchers design PSC-derived cell replacement therapy for PD. We focus here on 4 such first-in-human begun US, Europe, Japan. provide an overview sources PSCs methods generate transplantation. discuss pros cons strategies allogeneic, immune-matched, autologous approaches novel overcoming rejection immune system. consider challenges safety efficacy durable engraftment, focusing genomics-based quality control assure will not become cancerous. Finally, since like these never been undertaken before, we comment value cooperation among rivals contribute advancements finally relief millions suffering

Язык: Английский

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Optical Genome Mapping Reveals the Complex Genetic Landscape of Myeloma

Cancers, Год журнала: 2023, Номер 15(19), С. 4687 - 4687

Опубликована: Сен. 22, 2023

Fluorescence in situ hybridization (FISH) on enriched CD138 plasma cells is the standard method for identification of clinically relevant genetic abnormalities multiple myeloma. However, FISH a targeted analysis that can be challenging due to complexity The aim this study was evaluate potential optical genome mapping (OGM) detect significant cytogenetic myeloma and provide larger pangenomic information. OGM analyses were performed CD138-purified 20 patients. successfully detected structural variants (SVs) (IGH MYC rearrangements), copy number (CNVs) (17p/TP53 deletion, 1p deletion 1q gain/amplification) aneuploidy (gains odd-numbered chromosomes, monosomy 13) classically expected with led 30% increase prognosis yield at our institution when compared FISH. Despite challenges interpretation calls CNV losses non-diploid genomes, has replace as care clinical settings efficiently change how we identify prognostic predictive markers therapies future. To knowledge, first highlighting feasibility utility

Язык: Английский

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Inborn errors of immunity underlie clonal T cell expansions in large granular lymphocyte leukemia

Journal of Clinical Investigation, Год журнала: 2025, Номер 135(9)

Опубликована: Май 1, 2025

BACKGROUNDT cell large granular lymphocyte leukemia (T-LGLL) is a lymphoproliferative disorder of cytotoxic T lymphocytes (CTLs), often with gain-of-function STAT3 mutations. T-LGLL represents unique model for the study persistent CTL expansions. Albeit autoimmunity implied, various paradoxical observations led us to investigate whether immunodeficiency traits underpin T-LGLL.METHODSThis comprehensive immunogenomic 92 consecutive patients from cohort full laboratory-clinical characterization (n = 271). Whole-exome profiling variants associated inborn errors immunity (IEI) and somatic mutations in lymphoid drivers was analyzed. Single-cell RNA-Seq TCR-Seq samples cancer lines were utilized establish biological correlations.RESULTSLymphocytopenia and/or hypogammaglobulinemia identified 186 241 (77%) patients. Genetic screening IEI revealed 43 rare heterozygous 38 different immune genes 34 (36%) (vs. 167/63,026 [0.26%] controls). High-confidence deleterious dominant, adult-onset IEIs detected 15 (16%) Carriers showed atypical features otherwise tied cryptic IEI, such as earlier onset, lower counts, mutational rate, higher proportions cytopenia/bone marrow failure than noncarriers. Somatic landscape, RNA-Seq, analyses supported imbalance caused by interactions drivers.CONCLUSIONSOur findings reveal that maladaptive expansions may stem open horizon clonal hematopoiesis bone failure.FUNDINGNIH; Aplastic Anemia MDS International Foundation; VeloSano; Edward P. Evans Instituto de Salud Carlos III; European Research Council; Area Network on Personalised Medicine; Academy Finland; Cancer Foundation Finland.

Язык: Английский

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Analytic Validation of Optical Genome Mapping in Hematological Malignancies

Biomedicines, Год журнала: 2023, Номер 11(12), С. 3263 - 3263

Опубликована: Дек. 9, 2023

Structural variations (SVs) play a key role in the pathogenicity of hematological malignancies. Standard-of-care (SOC) methods such as karyotyping and fluorescence situ hybridization (FISH), which have been employed globally for past three decades, significant limitations terms resolution number recurrent aberrations that can be simultaneously assessed, respectively. Next-generation sequencing (NGS)-based technologies are now widely used to detect clinically sequence variants but limited their ability accurately SVs. Optical genome mapping (OGM) is an emerging technology enabling genome-wide detection all classes SVs at significantly higher than FISH. OGM requires neither cultured cells nor amplification DNA, addressing culture biases. This study reports clinical validation laboratory-developed test (LDT) according stringent regulatory (CAP/CLIA) guidelines SV different In total, 60 cases with malignancies (of various subtypes), 18 controls, 2 cancer cell lines were this study. Ultra-high-molecular-weight DNA was extracted from samples, fluorescently labeled, run on Bionano Saphyr system. A total 215 datasets, Inc.luding replicates, generated, analyzed successfully. Sample data then using either disease-specific or pan-cancer-specific BED files prioritize calls known diagnostically prognostically relevant. Sensitivity, specificity, reproducibility 100%, 96%, Following validation, 14 10 controls outside laboratories showing 96.4%. found more relevant compared SOC testing due its resolution. The results demonstrate superiority over traditional accurate diagnosis

Язык: Английский

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Clinical Utility of Optical Genome Mapping as an Additional Tool in a Standard Cytogenetic Workup in Hematological Malignancies

Cancers, Год журнала: 2025, Номер 17(9), С. 1436 - 1436

Опубликована: Апрель 25, 2025

Background and Objective: The primary objective of this study is to evaluate the added value optical genome mapping (OGM) when integrated into standard cytogenetic workup (SCGW) for hematological malignancies. Methods: cohort comprised 519 cases with different types OGM SCGW (including G-banded karyotyping fluorescence in situ hybridization) were performed on blood and/or bone marrow. analytical sensitivity OGM, defined as detection all additional cytogenomic aberrations, its clinical utility, referring aberrations diagnostic, prognostic, or therapeutic significance, assessed. Results: led increased utility 58% 15% cases, respectively. varied across malignancies, highest T-lymphoblast leukemia (52%), followed by mixed phenotype acute (43%), B-lymphoblastic (37%), other B-cell lymphomas (22%), mature T-cell leukemia/lymphoma (20%), chronic lymphocytic (14%), myeloid (13%), multiple myeloma mantle cell lymphoma (8%), myelodysplastic/myeloproliferative neoplasms (6%), myelodysplastic syndrome (5%), myeloproliferative (0%). Conclusion: Compared SCGW, detects approximately cases. provides at varying rates Given these differences, strategic triaging can help maximize focusing diseases where it offers most significant benefit.

Язык: Английский

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A case series of joubert syndrome evaluated with whole exome sequencing and the utility of optical genome mapping in the diagnosis

Neurogenetics, Год журнала: 2025, Номер 26(1)

Опубликована: Май 31, 2025

Язык: Английский

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Genomic technologies for detecting structural variations in hematologic malignancies

Blood Research, Год журнала: 2024, Номер 59(1)

Опубликована: Фев. 13, 2024

Genomic structural variations in myeloid, lymphoid, and plasma cell neoplasms can provide key diagnostic, prognostic, therapeutic information while elucidating the underlying disease biology. Several molecular diagnostic approaches play a central role evaluating hematological malignancies. Traditional cytogenetic assays, such as chromosome banding fluorescence situ hybridization, are essential components of current workup that guide clinical care for most hematologic However, each assay has inherent limitations, including limited resolution detecting small low coverage, only detect alterations target regions. Recently, rapid expansion increasing availability novel comprehensive genomic technologies have led to their use laboratories management translational research. This review aims describe relevance malignancies introduce may facilitate personalized tumor characterization treatment.

Язык: Английский

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Genomic structural variants analysis in leukemia by a novel cytogenetic technique: Optical genome mapping

Cancer Science, Год журнала: 2024, Номер 115(11), С. 3543 - 3551

Опубликована: Авг. 24, 2024

Abstract Genomic structural variants (SVs) play a pivotal role in driving the evolution of hematologic malignancies, particularly leukemia, which genetic abnormalities are crucial features. Detecting SVs is essential for achieving precise diagnosis and prognosis these cases. Karyotyping, often complemented by fluorescence situ hybridization and/or chromosomal microarray analysis, provides standard diagnostic outcomes various types front‐line testing leukemia. Recently, optical genome mapping (OGM) has emerged as promising technique due to its ability detect all identified other cytogenetic methods within one single assay. Furthermore, OGM revealed additional clinically significant clinical laboratories, underscoring considerable potential enhancing cases This review aims elucidate principles conventional techniques OGM, with focus on technical performance applications diagnosing prognosticating myelodysplastic syndromes, acute myeloid lymphoblastic chronic lymphocytic

Язык: Английский

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Optical Genome Mapping as a Tool to Unveil New Molecular Findings in Hematological Patients with Complex Chromosomal Rearrangements

Genes, Год журнала: 2023, Номер 14(12), С. 2180 - 2180

Опубликована: Дек. 5, 2023

Standard cytogenetic techniques (chromosomal banding analysis—CBA, and fluorescence in situ hybridization—FISH) show limits characterizing complex chromosomal rearrangements structural variants arising from two or more breaks. In this study, we applied optical genome mapping (OGM) to fully characterize cases of at high resolution. case 1, an acute myeloid leukemia (AML) patient showing chromothripsis, OGM analysis was concordant with classic helped better refine breakpoints. The results 2, a non-Hodgkin lymphoma, were only partially agreement previous analyses define clonal heterogeneity, overcoming the bias related selection due cell culture techniques. both cases, led identification molecular markers, helping pathogenesis, classification, prognosis analyzed patients. Despite extensive efforts study hematologic diseases, standard methods display unsurmountable limits, while is tool that has power overcome these limitations provide higher As also shows defining regions repetitive nature, combining CBA obtain complete characterization would be desirable.

Язык: Английский

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Optical Genome Mapping: A Machine-Based Platform in Cytogenomics

Methods in molecular biology, Год журнала: 2024, Номер unknown, С. 113 - 124

Опубликована: Янв. 1, 2024

Язык: Английский

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